This invention relates to (1) the novel method of using .+-.phenylpropanolamine to induce mucous secretion in the upper airways of persons afflicted with sinusitis or otitis media characterized by retention of thickened mucus and respiratory secretions and (2) certain novel compositions of l(-)-norephedrine and a pharmaceutically acceptable excipient base.
Phenylpropanolamine is a sympathomimetic compound administered orally as an anorectic and as a nasal decongestant. The compound has two chiral centers as shown in the following structural formula (the two chiral carbons, labeled alpha and beta, are denoted by an asterisk): ##STR1##
This results in four optical isomers, listed as follows with their common names and absolute configurations:
______________________________________ Isomer Alpha Beta ______________________________________ d(+)-norephedrine S R l(-)-norephedrine R S d(+)-norpseudoephedrine S S l(-)-norpseudoephedrine R R ______________________________________
A substance that rotates plane-polarized light in a clockwise direction is said to be dextrorotatory and the rotation is said to be positive. A substance that rotates plane polarized light in a counterclockwise direction is said to be levorotatory and the rotation is said to be negative (Solomons, Organic Chemistry, p. 246 (1978)).
The most active isomers physiologically for known uses are those with the S-configuration on the beta carbon atom (Lasagna, Phenylpropanolamine--A Review, p.28 (1980)). These are l (-)-norephedrine d(+)-norpseudoephedrine. The d(+)-norpseudoephedrine isomer is a naturally occurring substance found primarily in the shrub Catha edulis and is used orally in Europe for its anorectic properties at a dose of about 40-50 mg/day. A racemic mixture of d(+)-norephedrine and l(-)-norephedrine, generally referred to as either +phenylpropanolamine or phenylpropanolamine, is marketed as an anorectic at a dose of about 50-75 mg/day, and as a nasal decongestant at a dose of about 75-150 mg/day.
The four isomers of phenylpropanolamine are described in the literature. However, these four isomers have never been suggested to have nasal mucosecretory effects. For example, U.S. Pat. No. 4,818,541 issued to Sanderson on Apr. 4, 1989, discloses a method of inducing anorexia or nasal decongestion by the transdermal administration of any of the four isomers of phenylpropanolamine.
Persons afflicted with sinusitis or otitis media may suffer from nasal congestion, eustachian tube congestion and retention of respiratory mucus. Many persons who suffer from sinusitis or otitis media have both upper respiratory congestion and retention of thickened respiratory secretions. Antimicrobials are used to treat the infection in sinusitis and otitis media while decongestants are used to treat the congestion. Medications that promote upper respiratory decongestion constrict blood vessels in the upper respiratory tract; this reduces the tissue volume and thus provides decongestion of congested tissues, such as tissues in the nose, eustachian tubes and sinuses.
The prior art teaches that the constriction of nasal blood vessels reduces fluid in nasal tissues. The fluid in these tissues has two sources: (1) transudation which is the loss of fluid from the nasal blood vessels into the nasal tissues and (2) active secretion from cells in the respiratory mucosa and the nasal glands that secrete mucus. In healthy persons, there is little transudation. But transudation is increased greatly during infection and inflammation when the blood vessels become more permeable. Decongestants reduce transudation by constricting nasal blood vessels.
Decongestants have not been considered to provide complete relief from nasal congestion and retention of a particular thickened respiratory secretion, thickened mucus, since they are not known to promote mucous secretion and elimination of the retained mucus. Enhanced active secretion of mucus from cells in the respiratory mucosa and the nasal glands that secrete mucus would be beneficial to a person with thickened retained secretions and/or infection. Increased mucous secretions would help liquefy any thickened retained secretions (especially in the sinuses) and hence facilitate their drainage. Increased mucous secretions would also increase the flux of antimicrobial molecules onto the mucosa to combat the cause of the infection. In particular, mucous secretions increase the flux of antibacterial molecules in the mucus that combat the cause of the infection and they help liquefy any thickened, retained secretions (especially in the sinuses) and hence facilitate their drainage.